The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing, in concert with the general rise in obesity. A fatty liver is substantially more susceptible to ischemic injury as compared to a normal liver, responding with increased cell death and commensurate liver dysfunction. Ischemic injury is commonly encountered clinically, influencing recovery from hepatobiliary surgery, systemic shock, and transplantation, and thus leads to increased morbidity and mortality in patients with NAFLD. The presence of steatosis is also detrimental in the setting of organ procurement as it increases the number of non-utilizable organs and limits the donor pool. Though the exact mechanism for the increased vulnerability of a steatotic liver to ischemic insults is not known, there is evidence to show that CD4+ T cells are centrally involved. The overall goal of this project is to define the role of the adaptive immune system, and in particular T cells, in mediating post ischemic injury of a steatotic liver. Utilizing a surgical model of partial hepatic ischemia, key molecules and pathways involved in T cell and steatotic hepatocyte crosstalk will be investigated. Preliminary data have shown that T cell activation in the setting of steatotic hepatocytes is distinct from tha seen with normal hepatocytes. The specific aims of this proposal will examine the mechanistic links between T cells (activation, repertoire, effector phenotype, and trafficking), and steatotic hepatocyte cell death following ischemia reperfusion injury, and in particular, identify translatable targets for therapeutic intervention. The applicant for this mentored career development award is a pediatric hepatologist with a proven track record of commitment to research in liver disease. With a unique niche, an excellent mentorship structure and a supportive environment, this research proposal will provide the necessary training and opportunity for the applicant to develop into an independent researcher and make a significant contribution to the field of hepatology. PUBLIC HEALTH RELEVANCE: People with non-alcoholic fatty liver disease (NAFLD) are substantially more vulnerable to multiple mechanisms of liver injury. The study of the immune mechanisms involved in hepatocyte death following fatty liver injury will provide insight into the critical pathways involved in NAFLD-related liver injury and unveil translatable strategies for therapeutic intervention.